Body fat accumulation and distribution varies across ethnic groups and may influence the prevalence of obesity-related cancers in different ethnicities. This proposal examines the association between adipose accumulation and distribution, the gut microbiome, and phenotypes associated with obesity related cancer risk in the Multi-Ethnic Cohort (MEC). As such, the gut microbiome represents a potentially modifiable obesity-associated factor that may affect cancer risk. The gut microbiome influences human metabolism via regulation of energy uptake from diet, interaction with signaling molecules involved in host fatty acid metabolism, and sub-chronic inflammation~a hallmark of obesity-related diseases. Sub-chronic inflammation may be indirectly mediated through microbially generated dietary metabolites and, directly mediated through activation ofthe innate immune system. For example, gut bacterial endotoxins bind with lipopolysaccharide binding protein (LBP) to Toll-like receptors (TLR) that activate NF 1 levels of cytokines. Variants in human genes related to fatty acid metabolism and innate immunity may alter the interaction of the host with the gut microbiome and alter inflammation associated with obesity-related cancer risk. This innovative project will use the MEC cohort to investigate the composition of the gut microbiome, using high throughput sequencing approaches, as an effect modifier of the relationship between diet, fat distribution, and cancer risk. We will: 1) identify gut microbial profiles associated with body fat amount and distribution in the 5 ethnic groups among the 2,000 MEC subjects re-contacted for this study and analyze 4,229 stool samples collected for the microbiome GWA study in project 2; 2) test the associations of these microbial profiles with diet and other lifestyle factors, and with intermediate cancer phenotypes (i.e., cytokines, adipokines, steroid hormones, insulin, IGF hormones, and LBP); 3) examine the association between circulating LBP and colorectal cancer, using a case-control study nested within the MEC and measuring LBP in plasma drawn before diagnosis from 1379 colorectal cases and 1379 controls; and 4) participate in analyses integrating the gut microbiome results with those generated in the other projects in order to clarify inter-relationships among variables across data dimensions and construct best predictive models of body fat amount and distribution, and of cancer risk.